DESCRIPTION (Adapted from applicant's description): Dr. Caprio's main Patient-oriented Research (POR) focuses on the identification of early metabolic disturbances implicated in the genesis of juvenile obesity. The studies proposed here are a natural extension of her previous work in this area. She will continue to determine whether hyperinsulmemia or insulin resistance is the primary defect that is present in "high-risk" lean children of obese parents compared to "low-risk" lean children of nonobese parents. Both groups of preadolescents will be followed into adolescence to determine the evolution of putative defects in insulin secretion and action. In addition, she plans to determine if increased intramyocellular lipid stores (IMCL) of the soleus muscle are linked to the insulin resistance of childhood obesity and whether defective catecholamine-induces stimulation of lipolysis might contribute to further weight gain in obese children. 1H-NMR spectroscopy will be used to non-invasiveley assess IMCL stores and microdialysis technique to perfuse the subcutaneous adipose tissue with specific Beta1 and Beta2 andrenoceptor agonists, while simultaneously sampling interstitial glycerol concentrations in obese and nonobese children. Given her longstanding interest in studying hormonal and metabolic changes associated with the onset of puberty, she is determining changes in leptin levels in relation to changes in body composition, energy expenditure, LH, FSH, and sex steroids in a cohort of pubertal girls followed throughout puberty. Future directions in POR include: 1) measurement of ATP synthesis in skeletal muscle of obese subjects with known mutation in uncoupling protein 3 (UCP3) by 31P-NMR spectroscopy; 2) metabolic studies to determine the pathogenesis of type 2 diabetes in children and 3) pharmacological treatment of type 2 diabetes in youth use of Pioglitazone to reverse or improve insulin resistance. The K24 aware will not only assist her in her research endeavors, but will allow her to continue to mentor new clinical-scientists in POR. In summary, the combination of the glucose clamping tracer techniques, NMR imaging and for the first time microdialysis and NMR spectroscopy, in these studies will provide the unique opportunity to advance the understanding of the underlying pathophysiology of juvenile obesity. The long-term goal is to generate data that will lead to the development of new strategies for the prevention and treatment of juvenile obesity and Type 2 diabetes in children.